An overview on the Peer Exchange series, "Managing OFF Episodes in Parkinson disease."
Daniel E. Kremens, MD, JD
Although levodopa remains the gold standard therapy in the treatment of Parkinson disease, patients often face an unpredictable waxing and waning of treatment effect. This phenomenon, referred to as OFF time, can have a debilitating impact on quality of life.
The best methods to address OFF episodes are often hotly debated, and a therapeutic pipeline for these episodes is underway. Currently, physicians have some management options to balance these transition periods between levodopa doses, although these options do have limitations.
To add to the conversation about the management of OFF episodes, NeurologyLive® was joined by a panel of movement disorder experts led by Daniel E. Kremens, MD, JD, codirector, Parkinson’s Disease and Movement Disorders Program, and associate professor of neurology, Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, Pennsylvania. Kremens led a discussion covering a number of topics, beginning with the goals of OFF episode management in patients with Parkinson disease.
As Stuart Isaacson, MD, director, Parkinson’s Disease and Movement Disorder Center of Boca Raton in Florida quickly pointed out, the first deter- mination made by the physician is the goals of management: defining the amount of attention OFF episodes should require, what the goal of treatment will be, and if any OFF time is acceptable.
The goal, Rajesh Pahwa, MD, the Laverne and Joyce Rider professor of neurology, chief, Parkinson’s Disease and Movement Disorder Division, and director, Parkinson’s Foundation Center of Excellence, University of Kansas Medical Center, noted, should be to get patients to no OFF time, although, he admitted the bar is set high.
“It’s like asking me or you, ‘Well, during the day, would be it OK if you couldn’t function well for an hour?,’” Pahwa explained. “We’re all going to say, ‘No, absolutely not. I want to function all day long.’ And especially if I told you the hour could happen sometime during the day, but I can’t tell you when it’s going to happen.”
One of the approaches to possibly address this phenomenon was continuous delivery of levodopa through the gastro-intestinal tract. The panel noted that although there has been some succes, data from a double-blind, placebo-controlled trial revealed that through a 3-month treatment period, OFF time was still occurring as reported in patient diaries. For patients with severe OFF periods, reduced OFF time with lower severity may come as a comparative relief. Deep brain stimulation has also been shown to allow for better function during OFF time, but not completely eliminate it.
“That’s why I go back to it’s the severity of OFF,” Pahwa said, noting that if the OFF effects are limited to a symptom such as light sleepiness, a patient may be able to overcome it with a solution as simple as a cup of coffee. However, if dopamine wears off and that causes significant impairment for the patient, the physician must address it.
“Sometimes, I try to give an analogy to patients to try to gauge the severity by thinking about driving to the store,” Isaacson said. “If the roads are open, you get there easily. But now, you have some traffic and it takes you longer. And this may be a degree of slowness. Sometimes, you get into a traffic jam and you don’t move at all, and you’re completely OFF.”
The key, Isaacson said, is getting patients to understand that there may be degrees of response to both medicine and OFF periods. This is often achieved through shared decision making with the patient. Peter LeWitt, MD, MMedSc, director, Parkinson’s Disease and Movement Disorders Program, Henry Ford Hospital, and professor of neurology, Wayne State University School of Medicine in Detroit, Michigan, explained the resulting cost-benefit ratio.
“You may have to keep up with a more compli- cated schedule,” LeWitt said. “You may have to anticipate an adverse effect like dyskinesia if you’re loading up on extra medicine. But if your goal is to get to that store and not miss the sale, that’s an important part of patient decision making.”
The decision-making process regarding how to use medications is a complex interaction, LeWitt said. The physician needs to know how much involvement the patient wants in providing feedback and how much they want their family to be observers of their life to look out for signs that might require medical attention. With limited time, clinicians must work with every tool they have, including nurse prac- titioners, home diaries, and patient portals, among others.
“It really shows the value of shared clinical decision making,” Isaacson said. “While sometimes it’s hard to share, or there’s not enough time to share fully, patients have to be involved in this decision making. We can’t always judge, by knowing OFF, whether OFF needs to be treated for that patient.”
Kremens said that the ultimate goal is to set realistic expectations “Even with optimal management, sometimes the road is closed,” Kremens said. “There are issues with the blood—brain barrier that need to be addressed with Parkinson. So even with the best therapies, optimized medicine, some patients are still going to experi- ence these episodes.”
The panelists then shifted the discussion toward different management options with adjunctive dopamine agonists. Isaacson noted that although much of the past approach has been aimed at finding the optimal dose level, spacing, and fractionating, adjunctive options have now made their way to the physician’s arsenal.
These medicines include once-per-day therapies as well as on-demand treatments, and although the decisions to use either vary, one thing is certain, as Pahwa pointed out. Adding in more levodopa, while effective, ultimately leads to more fluctuation and more OFF time.
“We have to think about all of these different ideas and then also think about the mechanisms of OFF and the value, sometimes, for patients in using a nonoral medication,” Isaacson said. “Now we have a new era that’s going to be heralded with infusion therapies, where we try to keep patients ON all the time—and management is complicated.”
Jill M. Giordano Farmer, DO, MPH, assistant professor of neurology and director, Parkinson’s Disease and Movement Disorder Program, Global Neurosciences Institute in Philadelphia, Pennsylvania, explained that one of the ways to distill the complexity is to begin with the amount of OFF time occurring. This, she said, can lead to differing decision-making paths.
“Ideally speaking, if our goal is to not necessarily eliminate OFF but to practically manage it as best as possible, the best option might not necessarily be an on-demand. It might just need to be a revamp of the scheduling of the medications that they’re already on,” Giordano Farmer said.
Isaacson and LeWitt mentioned that challenges with adherence can also come up with additional dosing, and Pahwa noted that even long-acting preparations, which can address that adherence issue, are accompanied by their own set of obstacles. There are other therapeutic classes as well, such as dopamine agonists, monoamine oxidase-B (MAO-B) inhibitors, and catechol-o-methyl transferase (COMT) inhibitors, as Giordano Farmer pointed out.
Pahwa noted 2 major challenges with dopamine agonists: hallucination issues with older patients and compulsive disorders in younger ones. He explained that the literature suggests up to 20% of patients on dopamine agonists can have gambling, shopping, sexual, and other compulsions, which often go unmentioned—a generalization, for sure, but a possibility, the panel declared.
“But there isn’t evidence that they protect against motor fluctua- tions or dyskinesias, as was the past marketing-driven hope, which tells us that they are adjunctive therapies that are quite useful,” LeWitt said. “They clearly have a much longer duration of action, even in oral forms. But they join the COMT and MAO-B inhibitors as other ways to stretch out the effects of levodopa. This is the bottom line that comes from studies. Another thing that many clinicians may not be aware of is, probably sometime in the next year or 2 in the United States, we may have another COMT inhibitor as well as a once-a-day therapy that could also help us treat OFF time.”
Kremens raised the use of nondopaminergic agents, which include those such as the adenosine A2A receptor antagonist istradefyl-line, which has been shown to improve ON time for patients who are taking multiple medications. This is coupled by the fact that it is better tolerated than the MAO-B inhibitors, there are no drug inter- actions, and the effect appears to be fairly rapid in onset. As LeWitt puts it, it offers a sort of an “all-or-none” effect.
The 1 downside that is obvious, the group pointed out, is the possible enhancement of dyskinesia throughout treatment. “And of course, what do you do with dyskinesias? You lower the levodopa dose,” LeWitt said.
In addition, amantadine, in both immediate-release and extended-release formulations (along with a bedtime high dose), is available for physicians to prescribe. Isaacson pointed out that glutamatergic mechanisms are also a rational way of thinking about treatment.
“The fascinating thing, to me, is it improves OFF time in patients who are on all these other medications in the studies,” LeWitt said. “It’s a unique additive effect, or synergistic effect—it isn’t this choice or the other. Going back to the notion of polypharmacy sort of makes sense if you read into the studies and look at what patients have been tested with. They’ve been on a lot of different drugs, but they do better.”
Amantadine’s extended-release formulation was shown in bedtime studies to decrease OFF time and dyskinesia and is the only medication to do so.
“The other interesting part is, when we looked at studies for which we started drugs for OFF time, patients have 6 hours of OFF time, but when we look at a drug for dyskinesias, patients only had 3 hours of OFF time,” Pahwa pointed out. “In spite of 3 hours, we
were able to reduce it by 1 hour. Now whether that is because these patients were more optimally treated or whether the drug had unique nondopaminergic effects, we don’t know. But it brings up an interesting point, that every patient out there doesn’t have 6 hours of OFF time when they get put in a clinical trial. I think those are the ones who are really undertreated. If we are treating them adequately and the dyskinesia is an issue, their OFF time is also less.”
This is all part of the balancing act, Isaacson noted. Those with OFF time will also invariably have dyskinesia at a certain levodopa dose, and likewise, patients with dyskinesia, at a lower dose, will have OFF time. The positive, Kremens said, is that the nondopa- minergic therapies and infusion therapies give physicians another way of addressing the symptoms.
To view the entire Peer Exchange, “Managing OFF Episodes in Parkinson Disease,” click here.